Chemotherapy in Advanced Nasopharyngeal Cancer

Drs. Ali and Al-Sarraf have provided a comprehensive review on the treatment of nasopharyngeal cancer. They conclude that chemotherapy is an integral part of treatment for recurrent/metastatic disease and for locally advanced disease (stages III and IV).

For recurrent/metastatic disease, the authors report that chemotherapy achieves a 15% to 20% long-term survival rate and possible cure. For locally advanced disease, they conclude that combination chemotherapeutic agents administered either neoadjuvantly, concomitantly with, or after radiotherapy appear to improve local control, decrease systemic metastasis, and improve chances of disease-free survival and overall survival in the majority of reported studies. We will address these issues later.

Justification for Chemotherapy

In theory, the use of chemotherapy in the treatment of nasopharyngeal cancer can be justified based on the following observations:

(1) Nasopharyngeal cancer is very chemoresponsive, with published reports of long-standing complete responses in the presence of distant metastases[1-3];

(2) Nasopharyngeal cancer has a high rate of distant metastases (30% to 40%[4]);

(3) Numerous single-arm studies or retrospective investigations (as shown in Table 3 of Drs. Ali and Al-Sarraf’s article) have reported excellent results using various forms of chemotherapy in addition to radiation therapy; and

(4) In some studies, chemotherapy has been shown to enhance local control for locally advanced nasopharyngeal cancer.[5,6]

If chemotherapy is effective in both enhancing the local control rate of radiotherapy and combating systemic metastases, logic suggests that chemotherapy should be integral in the treatment of locally advanced nasopharyngeal cancer. Given the considerations listed above, nasopharyngeal cancer should be the perfect setting in which to display the potential of chemotherapy. Nevertheless, the use of chemotherapy in locally advanced nasopharyngeal cancer remains the subject of much debate.

Treatment of Recurrent/Metastatic Disease

Drs. Ali and Al-Sarraf indicate that, in patients with recurrent/metastatic nasopharyngeal cancer, chemotherapy achieves a 15% to 20% long-term survival rate and possible cure. Regarding local recurrence without distant metastasis, some data indicate that reirradiation alone can achieve long-term control in up to 50% of patients.[7,8] As to distant metastasis, there is no doubt that chemotherapy is beneficial and can produce a 15% to 20% complete response (as shown in several series).

That said, are these complete responses truly long term? And can these patients with metastatic nasopharyngeal cancer be “cured,” as some authors have suggested, or are these patients merely in long-term remission?

Choo and Tannock reviewed the experience in treating recurrent or metastatic nasopharyngeal cancer at Princess Margaret Hospital in Canada.[9,10] Complete response rates were 18% and 12%, with two different cisplatin (Platinol)-based regimens. With their later regimen—CAPABLE (cyclophosphamide, Adriamycin [doxorubicin], Platinol [cisplatin], amethopterin [methotrexate], and bleomycin)—2 out of 41 patients were still in remission at 3.5 and 7.0 years, resulting in a long-term remission rate of 5%. Toxicities, however, were severe, with frequent mucositis, myelosuppression, and, in 4 patients, drug-related deaths.

At the Prince of Wales Hospital in Hong Kong, nasopharyngeal cancer patients with metastatic disease were treated using a multimodality approach with combinations of platinum-based chemotherapy, radiation therapy, and even surgical resections.[11,12] Of 247 patients, 17 (7%) survived 2 years or longer, and only 4 (1.6%) achieved a 5-year disease-free interval.

As shown in Table 2 of Drs. Ali and Al-Sarraf’s article, the complete response rate to chemotherapy is approximately 15% to 20%. As such, the Hong Kong data are disturbing, because only 7% of patients survived 2 years or longer, and only 1.6% of patients achieved a 5-year disease-free survival. Taking together the Hong Kong and Canadian data, is it realistic to claim that patients with metastatic nasopharyngeal cancer can be “cured” or enjoy long-term survival using chemotherapy?

Chemotherapy for Locally Advanced Nasopharyngeal Cancer

In the conclusion of their article, Drs. Ali and Al-Sarraf state that “in patients with locally advanced, previously untreated stage III or IV nasopharyngeal carcinoma, combination chemotherapy given prior to, concomitant with, or following curative total radiotherapy improved local control, decreased systemic metastasis, and produced improvements in disease-free and overall survival in the majority of the studies reported.” Is this statement supported by the results of the randomized trials presented in the article by Drs. Ali and Al-Sarraf?

The five randomized trials presented in the article are: (1) The International Nasopharynx Study Group (VUMCA) trial, 339 patients)[13,14]; (2) Chan et al (Hong Kong series, 82 patients)[15]; (3) The Asian-Oceanian Clinical Oncology Association Study (334 patients)[6]; (4) Rossi et al (Milan series, 229 patients)[16]; and (5) The Intergroup Study of North America (study 0099, 185 patients).[17,18] Of these five randomized trials, four showed no overall survival benefits with the use of irradiation plus chemotherapy.

Intergroup study 0099 was the only exception, but this study demonstrated a very poor relapse-free survival (23% at 3 years) and a very poor overall survival (44% at 3 years) for the radiation-only arm. In fact, the 80% 2-year overall survival rate of the Intergroup study’s chemoradiation group was almost identical to the 80.5% 2-year survival rate of Chan et al’s radiation-alone group.

With regard to relapse-free survival, only two of the above randomized trials (VUMCA and the Intergroup study) showed a relapse-free survival benefit with the use of chemotherapy. However, in the VUMCA trial, an excess proportion of treatment-related deaths occurred in the chemotherapy arm (8%), compared to the radiation-only arm (1%).

How should these results be interpreted? Are the beneficial effects of chemotherapy negated by the excess of treatment-related deaths? Or is it only those patients who can tolerate the combined-modality treatment will receive the benefits of increased relapse-free survival? With only one of five randomized trials showing overall survival benefits and two of five randomized trials showing relapse-free survival benefits, are we justified in claiming that chemotherapy provides benefits in the majority of studies?

Conclusion

Given the chemosensitive nature of nasopharyngeal cancer, the 15% to 20% complete response rate seen in patients with metastatic nasopharyngeal cancer who receive chemotherapy, and 15 to 20 years of clinical experience with platinum-based chemotherapy, it remains an enigma that only one randomized trial has shown an overall survival advantage for combined chemotherapy and radiation therapy over radiation therapy alone in the treatment of localized nasopharyngeal cancer.

References:

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2. Teo PML, Kwan WH, Lee WY, et al: Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer 77:2423-2431, 1996.

3. Chan AT, Teo PM, Leung TW, et al: The role of chemotherapy in the management of nasopharyngeal carcinoma. Cancer 82:1003-1012, 1998.

4. Fu KK: Combined-modality therapy for head and neck cancer. Oncology 11:1781-1796, 1997.

5. Teo PML, Chan ATC, Lee WY, et al: Enhancement of local control in locally advanced, node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43:261-271, 1999.

6. Chua DTT, Sham JST, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association’s randomized trial comparing cisplatin and epirubicin followed by radiotherapy vs radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 83:2270-2283, 1998.

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9. Choo R, Tannock I: Chemotherapy for recurrent or metastatic carcinoma of the nasopharynx: A review of the Princess Margaret Hospital experience. Cancer 68:2120-2124, 1991.

10. Tannock I: Chemotherapy for nasopharyngeal cancer: The CAPABLE regimen (cyclophosphamide, doxorubicin, cisplatin, methotrexate, and bleomycin) (abstract). Proc Am Soc Clin Oncol 15:916a, 1996.

11. Yeo W, Leung TWT, Leung SF, et al: Phase II study of combination carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma. Cancer Chemother Pharmacol 38:466-470, 1996.

12. Teo PML, Kwan WH, Lee WY, et al: Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer 77:2423-2431, 1996.

13. International Nasopharynx Cancer Study Group, VUMCA I Trial: Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV

(³ N2, M0) undifferentiated nasopharyngeal carcinoma: A positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 35:463-469, 1996.

14. El-Gueddari B: Final results of the VUMCA I randomized trial comparing neoadjuvant chemotherapy (CT) (BEC) plus radiotherapy (RT) to RT alone in undifferentiated nasopharyngeal carcinoma (UCNT) (abstract). Proc Am Soc Clin Oncol 17:1482a, 1998.

15. Chan ATC, Teo PML, Leung TWT, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33:569-577, 1995.

16. Rossi A, Molinari R, Boracchi P, et al: Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: Results of a 4-year multicenter randomized study. J Clin Oncol 6:1401-1410, 1988.

17. Al-Sarraf M, LeBlanc M, Giri PGS, et al: Chemoradiotherapy vs radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup Study 0099. J. Clin Oncol 16:1310-1317, 1998.

18. Al-Sarraf M, LeBlanc M, Giri PGS, et al: Chemo-radiotherapy (CT-RT) in patients with advanced nasopharyngeal cancer: Intergroup (0099), SWOG 8892, RTOG 8817, ECOG 2388, Progress report (abstract). Proc Am Soc Clin Oncol 17:385a, 1998.